A unifying theme emerging from our work is that in neuroimaging, as in life, the journey is often as important as the destination. Trajectories of brain morphometry, as opposed to snapshots in time, are more highly correlated with cognitive parameters, are better predictors of clinical outcome, and more robustly distinguish groups classified by genotype. To capture the path of development we follow people throughout their maturation by having them return for participation at approximately two-year intervals. During their visit to the NIH participants are assessed in three realms: (1) Brain Imaging, (2) Neuropsychology, and (3) Genetics. Brain imaging. Magnetic resonance imaging (MRI) combines a powerful magnet, radio waves, and sophisticated computer technology to create exquisitely accurate pictures of the anatomy and physiology of the brain. It does this without the use of ionizing radiation making it safe for scans of people of all ages. The scans are processed through a series of ever improving image analysis tools developed by collaborators throughout the world. The output of the analytic tools allows us to compare the anatomy and physiology of brains between groups or within an individual over time. By morphing between images acquired at different ages we can create movies of brain development as can be seen at http://www.nimh.nih.gov/videos/press/prbrainmaturing.mpeg. Neuropsychology. For our studies of typical development we begin with an initial phone screening followed by questionnaires mailed to parents and teachers and then the in-person visit to the NIH. Once accepted into the study participants undergo a collection of psychological tests, including a standard IQ test. The specifics of the testing vary by diagnostic group but in general cover domains of language, executive, and social functions. Genetics. We request that participants provide a DNA sample via a blood draw (in which lymphoblasts can be immortalized to provide genetic testing for ongoing future analysis) or if they prefer not to have a blood draw via saliva. By combining data from these three realms we hope to gain insight into the dynamic interplay between brains, genes, and behavior in the developing brain. Key Findings and Recent Results from Project 1 Mapping Developmental Trajectories of Brain and Behavior in Health and Illness Prior work from our group has established age related increases in white matter volumes and inverted U shaped trajectories for cortical and subcortical gray matter structures with relatively late maturation of higher association areas such as superior temporal lobe and the prefrontal cortex. Cortical regions with simpler laminar architecture (i.e. allocortex), including most limbic areas, show less complex growth trajectories than 6-layered cortical regions (i.e. isocortex). The relationship between typical adolescent brain changes and the emergence of psychopathology has been explored. Publications in the past year have: (1) reviewed and summarized past contributions of structural MRI studies of pediatric brain development and speculated on future directions of the field (Ref 3);(2) examined the relationship between cortical surface area, cortical thickness, and cortical volume during typical development (Ref 10);(3) reported a relationship between the size and shape of the basal ganglia and repetitive behavior in autism spectrum disorder (Ref 2);(4) demonstrated differences in developmental trajectories of the corpus callosum between children with ADHD vs controls (Ref 5);described age-related temporal and parietal cortical thinning in autism spectrum disorders (Ref 12);(5) used cortical thickness development data to support a dimensional view of ADHD (Ref 11);(6) examined the effect of parental age on cortical development (Ref 13);and (7) applied graph theoretical approaches to discern connectivity differences in functional brain networks between those with childhood-onset schizophrenia and controls (Ref 1). Key Findings and Recent Results from Project 2 - Male/Female Differences in Brain Development Sexual dimorphism of the developing brain is especially pertinent for child psychiatry because nearly all neuropsychiatric disorders of childhood demonstrate striking male/female differences with respect to age of onset, prevalence, and symptom patterns. Publications within the past year: (1) reported the largest neuroimaging study to date describing male/female differences in the developing adolescent brain (Ref 9);(2) examined the relationship between alleles of the androgen receptor gene and sexually dimorphic human cortical maturation during adolescence (Ref 9);and (3) characterized executive function in Klinefelter (XXY) Syndrome with and without comorbid ADHD (Ref 6). Key Findings and Recent Results from Project 3 - Genetic and Environmental Influences on Brain Development By comparing how alike identical twins (monozygotic) are to how alike fraternal twins (dizygotic) are we can begin to quantify the extent to which differences are due to genetic or environmental factors. Current sample size from the ongoing longitudinal study is approximately 250 twin pairs. Key findings: (1) heritability is high and shared environmental effects low for most brain morphometric measures;(2) the cerebellum has a distinct heritability profile;(3) genetic and environmental factors contribute to the development of the cortex in a regional and age specific manner;and (4) shared genetic effects account for more of the variance than structure specific effects. Multivariate analyses indicate that 60% of cortical thickness variance is accounted for by a single genetic factor and that five distinct groups of brain measures are influenced by shared genetic and environmental factors. Understanding influences on trajectories of brain development may shed light on the emergence of psychopathology during childhood and adolescence and ultimately may guide therapeutic interventions. Publications in the past year have: (1) examined the effects of genetic variation on developmental trajectories of anatomic brain development (Ref 4);(2) reviewed developmental considerations of gene by environment ineractions (Ref 7);and (2) explored the relationship between Catechol-o-methyl transferase (COMT) val(158)met polymorphism and adolescent cortical development in patients with childhood-onset schizophrenia, their non-psychotic siblings, and healthy controls (Ref 8). Impact: The Brain Imaging project has had a high impact relative to the resources allocated having generated over 200 papers and 15,000 citations since its inception in 1989. Results of the studies, particularly regarding adolescent brain development, have generated wide spread public interest and discussion affecting social, educational, and judicial realms. The findings have helped spawn other research initiatives, both nationally and internationally, to replicate and extend the findings. Data from the typically developing children and adolescents have been widely used as a comparison group for clinical populations. Collaborative studies have been published with over 400 different investigators representing over 50 universities. The long term nature of the study, the emphasis on typical development, and extensive data sharing/collaboration make the Brain Imaging projects well-suited for the Intramural program.